It has been estimated that in the US between 1 and 2 million people currently suffer from the progressive dementia, Alzheimer's Disesase (AD). In the absence of definitive laboratory tests, confirmation of a diagnosis of AD can only be made post mortem and is based on the presence of the characteristic triad of lesions: amylois plaques, neurofibrillary tangles and granulovacuolar degeneration. Correlations between the extent of dementia in AD and the number of plaques found post mortem suggest that an understanding of the biosynthetic origin and processing of the amyloid precursor portein and the nature and function of this protein would provide important insights into the pathogenesis of AD. Assuming that amyloidosis in AD arises from an increased klevel of a circulating precursor, assays for this protein may lead to the development of a diagnostic test. This proposal is concerned with the isolation and characterization of the amyloid protein and precursor in AD using biochemicalk and immunochemical techniques, and with the determination of their distribution in normal and diseased brain tissue. Preliminary studies with antibody to a synthetic peptide corresponding to the amino terminus of the AD amyloid peptide show a selective reaction with amyloid plaques, glial cells and blood vessels in AD brain. The determination of the complete amino acid sequence of this small protein would allow the synthesis of the protein for unique studies on the molecular basis of amyloidogenicity, as well as the facile preparation of reagents for assay. Neither general nor specific mechanisms for the formation of amyloid are known, although participation of phagocytic cells is generally assumed. Possible pathways for the immune and non-immune stimulation of such cells include antibody and the complement system. The involvement of the complement system has been implicated in AD indirectly by genetic and directly by immunohistochemical analyses. This study will include a re-evaluation of the interactions of complement, specifically C4, in this disorder, both in terms of the genetic basis and of the local synthesis and function of C4 in the nervous system. Considerablke emphasis will be placed on a detailed analysis of the histopathological distribution of amyloid antigens, immunoglobulin and complement components in normal, AD and other diseased brain tissue. Where possible correlations will be made with the clinical progression of the disease in particular patients who come to autopsy. Other studies will address the role of the olfactory system as the site of primary involvement.